The program comprises 7 major subthemes - 4 projects, 2 specific cores and one technical development program. The leader of each team has specific expertise in one area of clinical medicine, immunology, cell biology and/or molecular biology. Each on their own has made a significant contribution to the bigger picture of viral pathogenesis in hepatitis C. The key feature of this consortium is that these have been blended to create a scientific team which is more than the sum of its parts, as will be detailed below. Specifically we propose to:- 1. Define the role of the hepatocyte as a key player in innate and adaptive immune responses (Project 1 Chung) 2. Define the specific qualities of tissue homing T cell populations in relation to hepatitis C infection (Project 2, Klenerman). 3. Define the functional capacity of intrahepatic T cell populations in persistent infection (Project 3, Lauer/Wherry). 4. Define the impact of T cell selection pressure on viral sequence evolution and the fitness landscape (Project 4, Allen/Henn). 5. Create a panel of reagents to modulate the surface signaling platform of T cells and antigen presenting cells (Core C/Freeman). 6. Create a library of tissue and cells from well defined clinical cohorts for experimental use (Core D/Misradji). 7. Develop a platform technology to examine and modulate critical signaling pathways that limit the adaptive immune response (TDP/Haining).